Magister Public Health - MPH / Introduction: The control of type 2 diabetes mellitus (T2DM) is pivoted on adherence to a healthy lifestyle (healthy diet, physical activity and non-smoking). Zimbabwe reports a high burden of T2DM related complications suggesting an increased inability by patients to control their blood glucose levels. This study, therefore, sought to describe the healthy lifestyle practices of T2DM patients in Harare, Zimbabwe and associate these practices with their glycated haemoglobin (HBA1C) levels, a marker for the control of diabetes. Methodology: A descriptive cross-sectional study was done. Participants were T2DM patients who were 18 years and older from two tertiary hospital diabetes clinics in Harare. Data collection was done using a structured questionnaire which was interviewer-administered along with height, weight and HBA1C measurements. Descriptive statistics were used to describe the study populations. Chi square test was used to calculate statistically significant associations between healthy lifestyle behaviours and demographics or HBA1C levels at the significant level of 0.05%.

Type 2 diabetes (T2D) is a metabolic disease that results from complex interactions between the environment, the genetic variation and epigenetic regulation of gene expression in individuals. Beta-cell dysfunction and insulin resistance are regarded as the hallmarks of the disease as the common presentation of T2D is the inability of beta-cells to adequately respond to the insulin demands of the body. The prevalence of T2D in Africa, and particularly South Africa, is on the rise. This is very likely the result of the combination of genetic susceptibility with increasing availability and accessibility of relatively cheap, highly palatable, calorie-dense meals with no corresponding lifestyle adjustment. This study aims to utilize available data from GWAS and gene expression arrays to identify potential variants that likely influence T2D susceptibility in African populations. Two public data repositories were mined – the National Center for Biotechnology Information’s (NCBI) Gene Expression Omnibus (GEO) and the National Human Genome Research Institute’s (NHGRI) GWAS Catalog. The criteria for selecting the studies for inclusion were based on ten descriptive T2D-related terms taken from the GWAS catalog’s pre-defined search categories. These terms were also applied to the selection of gene expression studies in GEO. These terms are: “fasting glucose-related traits”, “fasting insulin-related traits”, “fasting plasma glucose”, “insulin resistance/response”, “insulin traits”, “diabetes-related insulin traits”, “pro insulin levels” “Type 2 diabetes”, “type 2 diabetes and 6 quantitative traits” and “type 2 diabetes and other traits”. Ten Affymetrix platform-based studies in human tissues were chosen from GEO using these criteria. A Benjamin-Hochberg adjusted p-value of 0.05 was set as a cut-off for significant differentially expressed genes (7,887 genes) with 497 genes occurring in two or more studies, based on tissue- or array-type, considered candidates for downstream analysis. The GWAS catalogue presented 175 “reported” genes and 218 SNPs from 51 studies matching the set T2D-related criteria. Functional analyses done with the Database for Annotation, Visualization and Integrated Discovery (DAVID) on both the GWAS and expression studies genes lists,

by Mui Kin Tung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1993. / Includes bibliographical references (leaves 97-113). / Chapter CHAPTER 1: --- INTRODUCTION --- p.1 / Chapter CHAPTER 2: --- LITERATURE REVIEW --- p.5 / Chapter 2.1 --- ION TRANSPORT SYSTEMS IN HUMAN ERYTHROCYTES --- p.6 / Chapter 2.1.1 --- "Sodium Pump (Na+,K+-ATPase)" --- p.6 / Chapter 2.1.2 --- Passive Sodium Transport Systems --- p.9 / Chapter 2.1.2.1 --- Sodium-potassium-chloride cotransport system --- p.9 / Chapter 2.1.2.2 --- Sodium-lithium Countertransport --- p.13 / Chapter 2.1.3 --- Ouabain- and Frusemide-Resistant Passive Effluxes --- p.17 / Chapter 2.2 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN ESSENTIAL HYPERTENSION --- p.17 / Chapter 2.2.1 --- "Sodium Pump (Na+, K+-ATPase) in Essential Hypertension" --- p.18 / Chapter 2.2.2 --- Sodium-Potassium-Chloride Cotransport in Essential Hypertension --- p.20 / Chapter 2.2.3 --- Sodium-Lithium Countertransport in Essential Hypertension --- p.23 / Chapter 2.2.4 --- Passive Ion Fluxes in Essential Hypertension --- p.26 / Chapter 2.2.5 --- Intracellular Sodium Concentration in Essential Hypertension --- p.26 / Chapter 2.3 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN DIABETES MELLITUS --- p.27 / Chapter CHAPTER 3: --- MATERIALS & METHODS --- p.29 / Chapter 3.1 --- MATERIALS --- p.30 / Chapter 3.1.1 --- Choline Wash Solution (CWS) --- p.30 / Chapter 3.1.2 --- Lithium Loading Solution --- p.31 / Chapter 3.1.3 --- Choline Wash Solution with Ouabain (CWS-O) --- p.31 / Chapter 3.1.4 --- Sodium Containing Medium (SCM) --- p.31 / Chapter 3.1.5 --- Sodium Free Medium (SFM) --- p.31 / Chapter 3.1.6 --- Sodium Free Medium with Bumetanide (SFM-B) --- p.32 / Chapter 3.1.7 --- Preservation Solution --- p.32 / Chapter 3.2 --- STUDY POPULATION --- p.32 / Chapter 3.2.1 --- Control Subjects --- p.35 / Chapter 3.2.2 --- Patients with Essential Hypertension --- p.35 / Chapter 3.2.3 --- Diabetic Patients --- p.35 / Chapter 3.3 --- DETERMINATION OF ERYTHROCYTE INTRACELLULAR SODIUM AND POTASSIUM CONCENTRATIONS (Naic/Kic --- p.36 / Chapter 3.3.1 --- Preparation of Erythrocytes --- p.36 / Chapter 3.3.2 --- Preparation of Haemolysates --- p.38 / Chapter 3.3.3 --- Determination of Sodium and Potassium Concentrations in Haemolysates --- p.38 / Chapter 3.3.4 --- Determination of Haemoglobin Concentration in Haemolysates --- p.38 / Chapter 3.3.5 --- Evaluation of Erythrocyte Intracellular Sodium and Potassium Concentrations --- p.39 / Chapter 3.4 --- DETERMINATION OF ERYTHROCYTE PASSIVE POTASSIUM EFFLUX --- p.39 / Chapter 3.4.1 --- Determination of Potassium Concentrations in Supernatant --- p.40 / Chapter 3.4.2 --- Evaluation of Passive Potassium Efflux --- p.40 / Chapter 3.5 --- DETERMINATION OF ERYTHROCYTE SODIUM-LITHIUM COUNTERTRANSPORT (SLC) AND LITHIUM-POTASSIUM COTRANSPORT (LPC) --- p.41 / Chapter 3.5.1 --- Lithium Loading --- p.42 / Chapter 3.5.2 --- Determination of Haematocrit --- p.42 / Chapter 3.5.3 --- Preparation of Haemolysates --- p.42 / Chapter 3.5.4 --- Determination of the Lithium Concentration in Haemolysates --- p.43 / Chapter 3.5.5 --- Determination of Lithium Efflux --- p.43 / Chapter 3.5.6 --- Evaluation of Lithium Efflux Rate --- p.43 / Chapter 3.5.7 --- Evaluation of Intracellular Lithium Concentration --- p.44 / Chapter 3.6 --- VALIDATION OF METHODOLOGY FOR DETERMINATION OF ERYTHROCYTE SODIUM TRANSPORT SYSTEMS --- p.45 / Chapter 3.6.1 --- Effect of Time Course of Lithium Efflux --- p.45 / Chapter 3.6.2 --- Intracellular Potassium Concentration and Its Effect on Ouabain- and Frusemide-Resistant Passive Potassium Efflux --- p.45 / Chapter 3.7 --- PRESERVATION OF ERYTHROCYTES FOR DETERMINATION OF SODIUM TRANSPORT SYSTEMS --- p.51 / Chapter 3.8 --- PRECISION OF THE METHOD --- p.51 / Chapter 3.9 --- STATISTICS --- p.52 / Chapter CHAPTER 4: --- RESULTS --- p.56 / Chapter 4.1 --- POPULATION CHARACTERISTICS --- p.57 / Chapter 4.2 --- ERYTHROCYTE INTRACELLULAR LITHIUM CONCENTRATIONS AFTER LITHIUM LOADING --- p.57 / Chapter 4.3 --- RELATIONSHIP BETWEEN ERYTHROCYTE ION TRANSPORT PARAMETERS AND OTHER VARIABLES --- p.58 / Chapter 4.4 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN ESSENTIAL HYPERTENSION --- p.64 / Chapter 4.5 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN PATIENTS WITH DIABETES MELLITUS --- p.64 / Chapter 4.5.1 --- NIDDM Patients without Hypertension --- p.64 / Chapter 4.5.2 --- NIDDM Patients with Hypertension --- p.65 / Chapter 4.5.3 --- NIDDM Patients with and without Hypertension --- p.65 / Chapter 4.6 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN DIABETES MELLITUS PATIENTS WITH PROTEINURIA --- p.65 / Chapter 4.6.1 --- Clinical Features and Biochemistry Indices --- p.69 / Chapter 4.6.2 --- Ion Transport Systems and NIDDM Patients with Proteinuria --- p.69 / Chapter 4.7 --- EFFECTS OF TREATMENTS ON ERYTHROCYTE ION TRANSPORT SYSTEMS IN DIABETIC HYPERTENSIVE PATIENTS --- p.70 / Chapter 4.7.1 --- Effects of Diuretic Therapy --- p.70 / Chapter 4.7.2 --- Effects of Enalapril and Nifedipine Therapy --- p.74 / Chapter 4.7.3 --- Effects of Enalapril Therapy --- p.74 / Chapter 4.7.4 --- Effects of Nifedipine Therapy --- p.75 / Chapter 4.7.5 --- Comparison of the Effects of Enalapril and Nifedipine Therapy --- p.75 / Chapter CHAPTER 5: --- DISCUSSION --- p.81 / Chapter 5.1 --- SODIUM TRANSPORT IN ESSENTIAL HYPERTENSION --- p.82 / Chapter 5.1.1 --- Erythrocyte Sodium-Lithium Countertransport in Essential Hypertension --- p.82 / Chapter 5.1.2 --- Erythrocyte Sodium-Potassium Cotransport in Essential Hypertension --- p.86 / Chapter 5.1.3 --- Erythrocyte Intracellular Concentration of Sodiumin Essential Hypertension --- p.87 / Chapter 5.1.4 --- Erythrocyte Passive Potassium Efflux in Essential Hypertension --- p.90 / Chapter 5.2 --- SODIUM TRANSPORT SYSTEMS IN NON-INSULIN- DEPENDENT DIABETES MELLITUS (NIDDM) --- p.91 / Chapter 5.2.1 --- Sodium-Lithium Countertransport in Non-Insulin-Dependent Diabetes Mellitus --- p.91 / Chapter 5.2.2 --- Erythrocyte Lithium-Potassium Cotransport and Intracellular Sodium Concentration in Non-Insulin-Dependent Diabetes Mellitus --- p.93 / Chapter 5.3 --- EFFECT OF ANTIHYPERTENSIVE AGENTS ON ERYTHROCYTE SODIUM TRANSPORT SYSTEMS --- p.95 / REFERENCES --- p.98

The global prevalence of type 2 diabetes (T2DM) and obesity is increasing, with obesity the most important predisposing factor contributing to the development of T2DM. Epidemiological and genetic evidence supports a major genetic component in both multifactorial and heterogeneous disorders. The identification of disease susceptibility genes in humans could greatly assist in the elucidation of underlying pathophysiological mechanisms and allow the development of more effective preventative and therapeutic strategies for these conditions. Three candidate genes, uncoupling proteins 2 and 3 (UCP2; UCP3) and calpain 10 (CAPN10), are proposed and the rationale for their selection discussed. Gene variants were identified in UCP2 and UCP3. These variants were tested for association with T2DM, obesity and intermediate quantitative traits in a South Indian population and family collection, and also a cohort of British obese case/control subjects. No variant was associated with T2DM. However, investigations revealed positive associations with a UCP2 3'UTR 45bp Ins/Del and a novel UCP3 promoter variant (-55C/T) with variation in body mass (BMI) and fat distribution (WHR) respectively. The results support the view that uncoupling proteins may influence weight gain and hence progression to obesity/T2DM. A significant correlation with plasma leptin levels and the UCP2 Ins/Del variant might indicate one potential mechanism whereby weight could be modulated by uncoupling proteins. A linkage study in affected sibling pairs of North European descent, was negative for the putative T2DM susceptibility gene region, NIDDMI. In contrast, haplotypes of four sequence variants of a T2DM susceptibility gene (CAPN10) identified in this region positively associated with T2DM in a South Indian population. In conclusion, these investigations provide evidence that the three genes studied may contribute to susceptibility for development of T2DM or obesity. However, the findings are in agreement with the most likely genetic model for non-Mendelian complex diseases, that many genes are involved in determining susceptibility to disease with no single gene capable of determining the overall disease phenotype.

Type 2 diabetes mellitus affects over 100 million people worldwide. It is characterized by various metabolic abnormalities such as insulin resistance, aberrant insulin secretion, hyperglycaemia and a cluster of cardiovascular risk factors, including increased oxidative stress. It is associated with microvascular complications and increased potential of macrovascular disease. The aim of the studies described in this thesis was to test the hypothesis that oxidant stress contributes to an altered vascular function and impaired insulin regulation in a pre-diabetic animal model- the obese Zucker rats. The first objective was to develop new methods to measure endothelial function in animal disease models. Firstly, without autonomic control - the in situ perfused hindquarters, and secondly, with autonomic control - the in vivo Doppler ear blood flow. The obese Zucker rat was shown to have increased oxidative stress, as measured by plasma 8-epi-PGF2a,. It also had high insulin and glucose levels and impaired glucose disposal. Obese rats also had increased agonist-induced nitric oxide-dependent endothelial responses; these were further enhanced by insulin in a macrovascular preparation, but were impaired by insulin in a resistance vessel bed. Following dietary treatment with the antioxidants, the obese plasma insulin/glucose ratio was improved. However, vitamin E blunted the enhanced endothelial-dependent vasodilator responses, and decreased plasma levels of 8-epi-PGF2a. In contrast, pro-oxidant treatment with hydroquinone and buthionine-sulphoximine impaired the plasma insulin/glucose ratio, abolished endothelial hyperactivity but increased plasma 8-epi-PGF2a levels. Interestingly, fructose protected against pro-oxidant-induced increases in plasma 8-epi-PGF2a levels and further increases in glucose-induced plasma insulin. In summary the redox status in obese Zucker rats was modified with antioxidant and prooxidant treatment. This resulted in compensatory changes in glucose disposal and endothelial function. Impaired endothelial function may initiate "damage" especially in those individuals susceptible to syndrome X, leading to insulin insensitivity and vascular dysfunction in type 2 diabetes.

Gao, Zhibo. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 147-157). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Liu, Xin. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 157-164). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Background Obesity, insulin resistance and type 2 diabetes mellitus (T2DM) have been associated with endometrial cancer (EC). In this systematic review and meta-analysis we evaluated the effect of metformin on clinical outcomes in patients with EC and insulin resistance or T2DM. Methods Four research databases were searched for original articles published in all languages up to 30 October 2016. Outcomes of interest were overall mortality (OM), cancer-specific mortality, disease progression, and metastases. We performed a random effect meta-analysis of adjusted effects expressed as hazard ratios (HR); heterogeneity among studies was described with the I2 statistic. Results Of the 290 retrieved citations, 6 retrospective cohort studies in women with EC (n = 4723) met the inclusion criteria, and 8.9% to 23.8% were treated with metformin; OM data was available from 5 studies. In 4 studies of EC patients (n = 4132), metformin use was associated with a significant reduction in OM in comparison with not using metformin (adjusted HR [aHR] 0.64, 95% CI 0.45–0.89, p = 0.009). In three studies evaluating patients with EC and T2DM (n = 2637), metformin use was associated with a significant reduction in OM (aHR 0.50, 95%CI 0.34–0.74, p = 0.0006). There was low to moderate heterogeneity of adjusted effects across studies. There was no information about the effect of metformin on cancer-specific mortality, disease progression, or metastases. Conclusions Metformin treatment is associated with a significant reduction in OM irrespective of diabetes status in patients with EC. The survival benefit suggests that diabetes screening and maintenance of good glycemic control may improve outcomes in EC. / Revisión por pares

Type 2 diabetes and metabolic syndrome are the metabolic disorders which constitute a major public health problem in both developed and developing countries. Various studies have suggested the genetic susceptibility to the disorders. The main aim of the thesis was to investigate the putative association of single nucleotide polymorphisms with Type 2 diabetes (T2D), metabolic syndrome (MetS) and the major components of metabolic syndrome. This study used meta‐analysis, polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP) and Sanger sequencing methods to analyse the results. The single nucleotide polymorphism rs57829442 of peroxisome proliferator‐activated receptor‐γ coactivator‐1 (PPARGC1A) gene and its relation to risk of type 2 diabetes has been studied in the United Kingdom population. A meta‐analysis of genetic variant rs8192678 (Gly482Ser) of peroxisome proliferator‐activated receptor‐γ coactivator‐1 (PPARGC1A) gene and its association with the components of metabolic syndrome has been studied. An association of the genetic variants rs8192678 (Gly482Ser) of the PPARGC1A gene, rs7903146 of Transcription Factor 7 Like 2 (TCF7L2) gene, rs9939609 of Fat mass and obesity‐associated (FTO) gene and rs1801282 (Pro12Ala) of peroxisome proliferator‐activated receptor gamma (PPARG) gene with the metabolic syndrome and its components has been studied in the Nepalese population. The results showed that variant rs57829442 of PPARGC1A is not associated with T2D in the United Kingdom population. Further investigation with increased sample size is warranted. In the meta‐analysis, the variant rs8192678 (Gly482Ser) of PPARGC1A gene was found to be significantly associated with body mass index (BMI) in Asian populations under dominant genetic model, total cholesterol (TC) in non‐Asian population under recessive genetic model and with fasting plasma glucose (FPG) under a recessive model in overall and non‐Asian populations. No significant association of the variants rs8192678 (Gly482Ser), rs7903146, rs9939609 and rs1801282 (Pro12 Ala) was found associated with MetS under dominant, recessive, co‐dominant and additive models in the Nepalese population. However, the genotypes (AG and AA) of rs8192678 (Gly482Ser) had a statistically significant protective effect on systolic blood pressure. The genotypes with the risk allele of rs9930609 of FTO gene was significantly associated with weight, waist circumference and diastolic blood pressure under dominant genetic model and with BMI under both dominant and recessive genetic models in the Nepalese population. To the best of our knowledge, this is the first study to report the findings in the Nepalese population.

This thesis reviews and augments existing evidence surrounding the psychosocial aspects of living with Type 2 diabetes. There is a specific emphasis on the factors which underpin diabetes distress in individuals with Type 2 diabetes, which pertains also to the influence of partners or spouses on psychological adjustment to diabetes. This research develops and presents a conceptual framework of the key determinants of diabetes distress, providing focus and content for an intervention to address distress among couples living with Type 2 diabetes. Chapter 1 introduces the concept of diabetes distress; including prevalence, clinical relevance, and the cognitive, interpersonal and behaviour factors which are believed to drive this condition-specific distress. There is also an emphasis on existing strategies to improve both psychological and medical outcomes in Type 2 diabetes, which identified a need to evolve psychosocial support for individuals who are struggling to manage diabetes. Importantly, this chapter provided a rationale and direction for the studies reported in prospective chapters. Chapter 2 broadens the focus of psychosocial support in diabetes, to consider also the importance of considering partners or spouses in interventions to improve health outcomes in the context of different chronic physical conditions. This systematic review conveys the benefits of partner inclusion in interventions and highlights a number of shortcomings pertaining to couples intervention work. In particular, the review identifies a scarcity of couples intervention work in the context of Type 2 diabetes. The cross-sectional questionnaire study in Chapter 3 captures the predictive influence of illness perception clusters, coping styles, and relationship quality on diabetes distress in individuals with Type 2 diabetes. Of note, this work identifies negative belief and coping patterns which coincide and exacerbate distress, and presents a novel method of distinguishing those most at risk of elevated diabetes distress. Chapter 4 investigates the influence of partners’ diabetes beliefs on diabetes distress over time. This study demonstrates the moderating influence of partners’ illness perceptions on the association between persons with Type 2 diabetes illness perceptions and diabetes distress, and reveals that such effects persist overtime. Furthermore, Chapter 5 explores narratives of diabetes distress among couples living with Type 2 diabetes and among healthcare professionals, by means of individual semi-structured interviews and focus groups. Expanding on the findings of Chapters 3 and 4, this qualitative work compares experiences of distress from the perspectives of individuals with diabetes and those who support them in a personal and professional capacity, in an attempt to understand how communication and interpersonal conflicts might emerge in day to day life. Importantly, Chapter 5 discerns a perceived need for an intervention to reduce diabetes distress in individuals with Type 2 diabetes and their loved ones, and provides direction for the design and implementation of an intervention of this nature. Chapter 6 draws upon existing and primary evidence pertaining to the cognitive, interpersonal, and behavioural factors which underpin diabetes distress, and provides recommendations for the design and implementation of an intervention to address diabetes distress in couples living with Type 2 diabetes. The feasibility study described in Chapter 7 assesses the acceptability, potential effectiveness, and practical implementation of a brief psychoeducational intervention to address diabetes distress in people with Type 2 diabetes and their partners or family members. The findings of Chapter 7 highlight important strengths and shortcomings of providing an intervention of this nature, which are expanded on in the main discussion in Chapter 8. Chapter 8 provides a broad overview of the rationale for this PhD research and reflects on the primary work undertaken to date. Crucially, this discussion chapter provides recommendations on how key strengths of the feasibility study described in Chapter 7 can be enhanced and how observed shortcomings can be addressed in future studies. Finally, there is consideration of how aspects of the intervention described in Chapters 6 and 7 may feasibly be incorporated into existing programmes of diabetes support.